A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia.

[waldenström macroglobulinemia]

Myeloid differentiation factor 88 (MYD 88 ) L 265 P somatic mutation is highly prevalent in Waldenström macroglobulinemia (WM ) and supports malignant growth through nuclear factor κB (NF-κB ). The signaling cascade (s ) by which MYD 88 L 265 P promotes NF-κB activation in WM remain unclear . By lentiviral knockdown or use of a MYD 88 inhibitor , decreased phosphorylation of the NF-κB gatekeeper IκB α and survival occurred in MYD 88 L 265 P-expressing WM cells . Conversely , WM cells engineered to overexpress MYD 88 L 265 P showed enhanced survival . Coimmunoprecipitation studies identified Bruton tyrosine kinase (BTK ) complexed to MYD 88 in L 265 P -expressing WM cells , with preferential binding of MYD 88 to phosphorylated BTK (pBTK ). Increased pBTK was also observed in WM cells transduced to overexpress L 265 P vs wild-type MYD 88 . Importantly , MYD 88 binding to BTK was abrogated following treatment of MYD 88 L 265 P-expressing cells with a BTK kinase inhibitor . Inhibition of BTK or interleukin-1 receptor-associated kinase 1 and 4 (IRAK -1 and -4 ) kinase activity induced apoptosis of WM cells , and their combination resulted in more robust inhibition of NF-κB signaling and synergistic WM cell killing . The results establish BTK as a downstream target of MYD 88 L 265 P signaling , and provide a framework for the study of BTK inhibitors alone , and in combination with IRAK inhibitors for the treatment of WM .